Breast cancer remains the major cause of cancer death in women in the developed world. Novel therapeutic modalities are needed for those patients in whom chemotherapy, hormonal treatment and external radiation therapy are not effective. Recently a new molecular target has been identified in 80% of mammary cancers in humans but not in normal/healthy breast tissue - mammary gland sodium/iodide symporter (mgNIS) which may open a new avenue in treatment of breast cancer with radioactive iodine 131-I. However, in the absence of prolonged biological retention of 131-I in NIS-expressing mammary tumors an isotope with shorter physical half-life and superior to 131-I decay properties, which can be transported by NIS may provide a better therapeutic option. We have recently showed that the powerful beta-emitter 188-Rhenium (188-Re) which has therapeutically useful emissions superior to those of 131-I, is also transported by NIS and will deliver several times higher radiation dose to the tumor in comparison with 131-I. We hypothesize that 188-Re will be more efficient than 131-I in elimination of NIS-expressing breast tumors in mice. We also hypothesize that the combination of dose fractionation/normal organ protection will increase 188-Re tumodcidal effect while decreasing the radiation dose to normal organs. To test these hypotheses we will start with evaluation of 188-Re and 131-I cell-killing impact on NIS-expressing cells of thyroid in normal mice under the conditions of suppressed organification. We will perform comparative 188-Re and 131-I therapy of xenografted breast tumors in nude mice including dose escalation and maximum tolerated dose determination. We will employ the combination of dose fractionation/stomach protection to protect the stomach from radiation. We wilt also perform comprehensive dosimetry calculations for future therapy of NIS-expressing breast cancers in humans. The Specific Aims of the project are: Aim 1 To compare cell-killing potential of 188-Rhenium versus 131-Iodine in NIS-expressing tissue in vivo using thyroid in healthy mice as a target organ. Aim 2 To evaluate the feasibility of using 188-REO4- as a tumoricidal agent in NtS-expressing breast cancer tumors in mice. The proposed research will provide data on interaction of a novel molecular cancer target - mgNiS with non-iodine therapeutic radioisotope and on its potential to eradicate breast tumors. The long-term goal of this research is to contribute to the development of a novel cost-effective radionuclide therapy for treatment of breast cancer and, possibly, for other NIS-expressing cancers such as thyroid cancer.